Amorphous onapristone compositions and methods of making the same

ABSTRACT

Amorphous forms of onapristone and methods of making such amorphous forms are provided. Amorphous forms can be characterized by their X-ray powder diffraction patterns and other properties.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/267,540, filed Dec. 15, 2015. The above referencedapplication is incorporated herein by reference as if restated in full.

All references cited herein, including but not limited to patents andpatent applications, are incorporated by reference in their entirety.

BACKGROUND

Onapristone (ONA)((8S,11R,13R,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one)is an anti-progestin drug and progesterone receptor antagonist has thefollowing structure:

Onapristone is known to be an amorphous compound. For example,Onapristone has previously been isolated as an amorphous solid and as ayellow oil. Neef, et al. Steroids, 1984, 44, 349; Neef, et al.,DE3321826. In contrast to onapristone, (3-Acyloxypropyl)-derivatives ofonapristone were identified as crystalline. See U.S. Pat. No. 4,780,461.Recently, however, crystalline forms of onapristone have beenidentified. See e.g., U.S. Patent Publication Number 2014/0271819.

The term “amorphous,” as used herein, refers to the non-crystalline formof a chemical compound. Whereas the crystalline forms of a compound arecharacterized by structures assembled by the repetitive building up offundamental units containing the molecules of the compound (known asunit cells), amorphous compounds have no such long-range repetitivestructure, and are characterized by short-range, random ordering.Consequently, the lack of crystalline structure inherent to an amorphouscompound may lead to significant differences in the physical andchemical properties of the compound, such as its solubility, dissolutionrate, stability, bioavailability, and efficacy.

The amorphous form of a drug substance can be compared to crystallineforms of the compound using by a variety of techniques including, butnot limited, to melting point, thermogravimetric analysis (TGA),differential scanning calorimetry (DSC), X-ray powder diffraction(XRPD), high performance liquid chromatography (HPLC), Raman microscopy,FT-IR spectroscopy, and solid-state nuclear magnetic resonance (ssNMR).The physical stability of the amorphous form of a compound can bemeasured, for example, under conditions where the temperature andhumidity in the environment are controlled for various time periods.

The term “co-precipitate” refers to the simultaneous precipitation ofmore than one compound together in a single-phase solid form from asolution. The term “precipitate” refers to the formation of a solid froma liquid solution. Precipitates can be used, for example, to modulatethe properties of a chemical compound (e.g., bioavailability,pharmacokinetics, stability).

SUMMARY

Aspects disclosed herein provide amorphous onapristone compositions andmethods of making amorphous onapristone including, for example, by (1)pH cycling, (2) solvation-desolvation, (3) spray-dryingonapristone/polymer mixtures, (4) solution-coprecipitation, and (4)solidification of hot melts.

One aspect provides methods of making amorphous onapristone by “pHcycling”. In this procedure, onapristone bulk drug substance isdissolved in a solvent, decreasing the pH of the resulting solution todissolve the compound, and subsequently increasing the pH of theresulting solution to form an amorphous precipitate.

Another aspect provides methods of making amorphous onapristone bydissolving onapristone in a suitable solvent, followed by evaporation ofthe solution to yield a solvate, and then desolvating the solvate undercontrolled conditions to yield amorphous drug substance.

Further aspects provide compositions comprising amorphous onapristoneand polymeric excipients. These compositions may be obtained, forexample, spray-drying or precipitation from a solution.

Yet another aspect provides methods of making amorphous onapristone by a“hot melt” process, whereby onapristone and various polymers are heatedto form a polymer melt where the onapristone is dissolved in theresulting mixture. The melt is subsequently cooled to obtain thecomposition. Compositions comprising onapristone and various polymersare also provided.

As described herein, amorphous onapristone can be prepared as a puredrug substance, either through the use of a pH-cycling method or bycontrolled desolvation of the methanol solvate of onapristone. ThepH-cycled product remains amorphous for extended periods of time. Forexample, the pH-cycled product has been shown to remain amorphous for atleast 16.5 months, while the solvation-desolvation product was shown toremain amorphous for at least 29 weeks (i.e., 7.25 months).

When spray-dried along with appropriate polymeric excipients,onapristone can be obtained in the form of an amorphous dispersion at a25% w/w drug loading level. Two such dispersions have been shown toremain amorphous for at least 15 months.

When processed using a hot-melt procedure together with appropriatepolymeric excipients, onapristone can be obtained in the form of anamorphous dispersion at a nominal 25% w/w drug loading level. Seven suchdispersions have been shown to remain amorphous for at least 8 weeks(i.e., two months).

Amorphous onapristone compositions as described herein, and madeaccording to methods described herein, are stable in their amorphousstate and retain their amorphous properties when stored under ambientconditions.

FIGURES

FIG. 1 shows exemplary X-ray powder diffraction patterns of onapristoneproduced by the pH-cycle method;

FIG. 2 shows exemplary X-ray powder diffraction patterns of 25% w/wonapristone dispersions (containing polyvinyl pyrrolidone VA64) producedby the spray-drying method, and stored for various time periods;

FIG. 3 shows exemplary X-ray powder diffraction patterns of 25% w/wonapristone dispersions (containing hydroxypropyl methylcellulosesuccinate M) produced by the spray-drying method, and stored for varioustime periods;

FIG. 4 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing Kollidon®® 30(polyvinylpyrrolidone)) produced by the hot-melt method, and stored forvarious time periods;

FIG. 5 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing polyvinylpyrrolidone K29/32) produced by the hot-melt method, and stored forvarious time periods;

FIG. 6 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing polyethyleneglycol 8000) produced by the hot-melt method, and stored for varioustime periods;

FIG. 7 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing polyethyleneglycol 3350) produced by the hot-melt method, and stored for varioustime periods;

FIG. 8 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing 27.1% w/wpolyvinyl pyrrolidone K29/32 and 72.9% w/w polyethylene glycol 3350)produced by the hot-melt method, and stored for various time periods;

FIG. 9 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing 49.3% w/wpolyvinyl pyrrolidone K29/32 and 50.7% w/w polyethylene glycol 3350)produced by the hot-melt method, and stored for various time periods;

FIG. 10 shows exemplary X-ray powder diffraction patterns ofapproximately 25% w/w onapristone dispersions (containing 73.5% w/wpolyvinyl pyrrolidone K29/32 and 26.5% w/w polyethylene glycol 3350)produced by the hot-melt method, and stored for various time periods;

FIG. 11 shows exemplary X-ray powder diffraction patterns of binaryonapristone dispersions containing Kollidon® 30 produced by thesolution-phase coprecipitate method, prepared to contain varying amountsof onapristone;

FIG. 12 shows exemplary X-ray powder diffraction patterns of binaryonapristone dispersions containing polyvinylpyrrolidone K29/32 producedby the solution-phase coprecipitate method, prepared to contain varyingamounts of onapristone;

FIG. 13 shows exemplary X-ray powder diffraction patterns of binaryonapristone dispersions containing polyethylene glycol 3350 produced bythe solution-phase coprecipitate method, prepared to contain varyingamounts of onapristone;

FIG. 14 shows exemplary X-ray powder diffraction patterns of binaryonapristone dispersions containing polyethylene glycol 8000 produced bythe solution-phase coprecipitate method, prepared to contain varyingamounts of onapristone; and

FIG. 15 shows exemplary X-ray powder diffraction patterns ofapproximately 25% onapristone ternary dispersions containing variousamounts of Kollidon® 30 and polyethylene glycol 8000 produced by thesolution-phase coprecipitate method.

DETAILED DESCRIPTION

Before describing several exemplary aspects described herein, it is tobe understood that the invention is not limited to the details ofconstruction or process steps set forth in the following description andexamples. The aspects described herein are capable of being practiced orbeing carried out in various ways. All publications, patents, and patentapplications cited herein are incorporated by reference in theirentirety.

Aspects described herein provide amorphous forms of onapristone whichhave advantageous properties including but not limited to increasedbioavailability, increased stability, increased dissolution rate, andincreased solubility. In one aspect, these properties relate toproperties that will impart advantages with respect to formulatingonapristone into a suitable dosage form.

Amorphous forms of onapristone have varying physical and chemicalproperties with respect, for example, solubility, melting temperature,and hygroscopicity, which may affect the stability of a particulardosage form of onapristone. Drug formulation and dosage form selectionhave a significant impact on the cost of manufacturing. Physicalproperties such as flow, particle size, surface area, and hardness maysignificantly impact the pharmacokinetics of the drug. For example, thedissolution and subsequent absorption of the drug in the body willaffect the maximum concentration in the blood, clearance of the drug,and whether the drug is resident in the body for the optimal period oftime.

In one aspect, amorphous onapristone is formed by adding onapristone towater, dissolving the onapristone in the water by adding one equivalentof an acid solution, and subsequently increasing the pH of the solutionby the addition of one equivalent of base. At the end of this process,an amorphous precipitate is formed which may be isolated andcharacterized. In another aspect, the XPRD pattern of the precipitatedonapristone does not produce any substantially sharp scattering peaks.The presence of a crystalline substance is indicated by the presence ofsharp peaks (i.e., those whose width at half-height is in the range of0.3 to 0.5 degrees 2θ) in an XRPD pattern, while the XRPD pattern of anamorphous substance is characterized by the presence of broad scatteringpeaks (i.e., those whose width at half-height is in the range of atleast 8 to 12 degrees 2θ).

In one aspect, the acid solution comprises any suitable acid (e.g.,hydrochloric acid (HCl), nitric acid (HNO₃), or sulfuric acid (H₂SO₄)).In one aspect, the acid is hydrochloric acid.

In another aspect, the base is any suitable base (e.g., sodium hydroxide(NaOH), potassium hydroxide (KOH), or ammonium hydroxide (NH₄OH)). Inone aspect, the base is sodium hydroxide.

In yet another aspect, the pH is reduced to pH=1 or below. In a furtheraspect, when the pH is raised, it is increased to pH=10 or above.

In another aspect, onapristone is first dissolved in methanol, and theresulting solution allowed to dry yielding an onapristone/methanolsolvate. If this resulting solvated form is heated at a temperaturesufficient to desolvate the solid (e.g., around 100° C.) for the minimalamount of time (e.g., less than 10 minutes), amorphous onapristone isformed.

Yet another aspect provides compositions comprising onapristone (25%) ina polyvinylpyrrolidone VA64 copolymer matrix (i.e., onapristone/PVP VA64).

Aspects provide methods of spray drying amorphous onapristone by spraydrying onapristone/PVP VA 64 from a solution comprising about 8% w/wsolids in methanol resulting in amorphous onapristone.

Another aspect provides compositions comprising onapristone andKollidon® (polyvinylpyrrollidone) 30 (onapristone/Kollidon® 30). Inanother aspect, the composition comprises about 0.255 g of onapristoneand about 0.777 g of Kollidon® 30.

Another aspect provides methods of making amorphous onapristone byheating onapristone/Kollidon® 30 until the Kollidon® 30 melts, forming amolten mixture wherein the onapristone is dissolved in the polymer melt.Next, the mixture is allowed to cool to room temperature and form aglassy solid of amorphous onapristone. In another aspect, theonapristone content of the glassy solid is about 24% w/w.

Another aspect provides compositions comprising onapristone andpolyethylene glycol 8000 (Onapristone/Kollidon® 30). In another aspect,the composition comprises about 0.241 g of onapristone and about 0.700 gof polyethylene glycol 8000.

Further aspects provide methods of making amorphous onapristone byheating onapristone/polyethylene glycol 8000 until the polyethyleneglycol 8000 melts forming a polymer melt, and the onapristone dissolvesin the polymer melt forming a mixture. Next, the mixture is allowed tocool to room temperature and form a glassy solid of amorphousonapristone. In another aspect, the onapristone content of the glassysolid is about 25% w/w.

Another aspect provides compositions comprising onapristone andpolyethylene glycol 3350 (onapristone/polyethylene glycol 3350). Inanother aspect, the composition comprises about 0.238 g of onapristoneand about 0.762 g of polyethylene glycol 3350.

Further aspects provide methods of making amorphous onapristone byheating onapristone/polyethylene glycol 3350 until the polyethyleneglycol 3350 melts forming a polymer melt, and the onapristone dissolvesin the polymer melt forming a mixture. Next, the mixture is allowed tocool to room temperature and form a glassy solid of amorphousonapristone. In another aspect, the onapristone content of the glassysolid is about 23% w/w.

Another aspect provides compositions comprising onapristone andpyrrolidone K29/32 (onapristone/pyrrolidone K29/32). In another aspect,the composition comprises about 0.249 g of onapristone and about 0.784 gof pyrrolidone K29/32.

Further aspects provide methods of making amorphous onapristone byheating onapristone/pyrrolidone K29/32 until the pyrrolidone K29/32melts forming a polymer melt, and the onapristone dissolves in thepolymer melt forming a mixture. Next, the mixture is allowed to cool toroom temperature and form a glassy solid of amorphous onapristone. Inanother aspect, the onapristone content of the glassy solid is about 24%w/w.

Another aspect provides compositions comprising onapristone, polyvinylpyrrolidone K29/32, and polyethylene glycol 3350(onapristone/pyrrolidone K29/32/PEG). In another aspect, the compositioncomprises about 0.258 g of onapristone, about 0.202 g of polyvinylpyrrolidone K29/32, and about 0.503 g of polyethylene glycol 3350. Inyet another aspect, the composition comprises about 0.242 g ofonapristone, about 0.373 g of polyvinyl pyrrolidone K29/32, and about0.384 g of polyethylene glycol 3350. In yet another aspect, thecomposition comprises about 0.241 g of onapristone, about 0.547 g ofpolyvinyl pyrrolidone K29/32, and about 0.197 g of polyethylene glycol3350.

Further aspects provide methods of making amorphous onapristone byheating onapristone/pyrrolidone K29/32 until the polyvinyl pyrrolidoneK29/32 and polyethylene glycol 3350 melts forming a polymer melt, andthe onapristone dissolves in the polymer melt forming a mixture. Next,the mixture is allowed to cool to room temperature and form a glassysolid of amorphous onapristone.

FIG. 1 shows X-ray powder diffraction patterns of onapristone asinitially produced by the pH-cycle method, and stored under ambientconditions for 25 weeks, 43 weeks, and 16.5 months.

FIG. 2 shows X-ray powder diffraction patterns of 25% w/w onapristonedispersions (containing polyvinyl pyrrolidone VA64) produced by thespray-drying method, and stored under ambient conditions for 12 weeks,20 weeks, 36 weeks, and 15 months.

FIG. 3 shows X-ray powder diffraction patterns of 25% w/w onapristonedispersions (containing hydroxypropyl methylcellulose succinate M)produced by the spray-drying method, and stored under ambient conditionsfor 12 weeks, 20 weeks, 36 weeks, and 15 months.

FIG. 4 shows X-ray powder diffraction patterns of nominal 25% w/wonapnstone dispersions (containing Kollidon® 30) produced by thehot-melt method, and stored under ambient conditions for 8 weeks and 8.5months.

FIG. 5 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing polyvinyl pyrrolidone K29/32)produced by the hot-melt method, and stored under ambient conditions for8 weeks and 8.5 months.

FIG. 6 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing polyethylene glycol 8000) producedby the hot-melt method, and stored under ambient conditions for 8 weeksand 8.5 months. The XRPD pattern for polyethylene glycol 8000 itself isshown for comparison purposes, demonstrating that all scattering peaksin the XRPD of the formulations were due entirely to the excipient.

FIG. 7 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing polyethylene glycol 3350) producedby the hot-melt method, and stored under ambient conditions for 8 weeksand 8.5 months. The XRPD pattern for polyethylene glycol 3350 itself isshown for comparison purposes, demonstrating that all scattering peaksin the XRPD of the formulations were due entirely to the excipient.

FIG. 8 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing 27.1% w/w polyvinyl pyrrolidoneK29/32 and 72.9% w/w polyethylene glycol 3350) produced by the hot-meltmethod, and stored under ambient conditions for 8 weeks and 8.5 months.The XRPD pattern for polyethylene glycol 3350 itself is shown forcomparison purposes, demonstrating that all scattering peaks in the XRPDof the formulations were due entirely to the excipient.

FIG. 9 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing 49.3% w/w polyvinyl pyrrolidoneK29/32 and 50.7% w/w polyethylene glycol 3350) produced by the hot-meltmethod, and stored under ambient conditions for 8 weeks and 8.5 months.The XRPD pattern for polyethylene glycol 3350 itself is shown forcomparison purposes, demonstrating that all scattering peaks in the XRPDof the formulations were due entirely to the excipient.

FIG. 10 shows X-ray powder diffraction patterns of nominal 25% w/wonapristone dispersions (containing 73.5% w/w polyvinyl pyrrolidoneK29/32 and 26.5% w/w polyethylene glycol 3350) produced by the hot-meltmethod, and stored under ambient conditions for 8 weeks and 8.5 months.The XRPD pattern for polyethylene glycol 3350 itself is shown forcomparison purposes, demonstrating that all scattering peaks in the XRPDof the formulations were due entirely to the excipient.

FIG. 11 shows X-ray powder diffraction patterns of onapristonedispersions containing Kollidon® 30 produced by the solution-phasecoprecipitate method. The nominal onapristone concentrations in thedispersions are indicated, and the XRPD pattern for Kollidon® 30 itselfis shown for comparison purposes.

FIG. 12 shows X-ray powder diffraction patterns of onapristonedispersions containing polyvinylpyrrolidone K29/32 produced by thesolution-phase coprecipitate method. The nominal onapristoneconcentrations in the dispersions are indicated, and the XRPD patternfor polyvinylpyrrolidone K29/32 itself is shown for comparison purposes.

FIG. 13 shows X-ray powder diffraction patterns of onapristonedispersions containing polyethylene glycol 3350 produced by thesolution-phase coprecipitate method. The nominal onapristoneconcentrations in the dispersions are indicated, and the XRPD patternfor polyethylene glycol 3350 itself is shown for comparison purposes(demonstrating that all scattering peaks in the XRPD of the formulationswere due entirely to the excipient).

FIG. 14 shows X-ray powder diffraction patterns of onapristonedispersions containing polyethylene glycol 8000 produced by thesolution-phase coprecipitate method. The nominal onapristoneconcentrations in the dispersions are indicated, and the XRPD patternfor polyethylene glycol 8000 itself is shown for comparison purposes(demonstrating that all scattering peaks in the XRPD of the formulationswere due entirely to the excipient).

FIG. 15 shows X-ray powder diffraction patterns of nominal 25%onapristone dispersions containing various amounts of Kollidon® 30 andpolyethylene glycol 8000 produced by the solution-phase coprecipitatemethod. The relative percentages of the two polymers are indicated.

The onapristone amorphous forms can be used to treat a patient in needof treatment as described herein. The terms “treat,” “prevent,” orsimilar terms, as used herein, do not necessarily mean 100% or completetreatment or prevention. Rather, these terms refer to various degrees oftreatment or prevention of a particular disease (e.g., 100%, 90%, 80%,70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%) as recognized in the artas being beneficial. The terms “treatment” or “prevention” also refer todelaying onset of a disease for a period of time or delaying onsetindefinitely. The term “treatment” or “treating” refers to administeringa drug or treatment to a patient or prescribing a drug to a patientwhere the patient or a third party (e.g., caretaker, family member, orhealth care professional) administers the drug or treatment.

The onapristone amorphous forms also encompass derivatives. In oneembodiment, the term “derivative” includes, but is not limited to, etherderivatives, acid derivatives, amide derivatives, ester derivatives andthe like. Methods of preparing these derivatives are known to a personskilled in the art. For example, ether derivatives are prepared by thecoupling of the corresponding alcohols. Amide and ester derivatives areprepared from the corresponding carboxylic acid by a reaction withamines and alcohols, respectively.

The onapristone amorphous forms also encompass hydrates or solvates ofonapristone amorphous or crystalline forms (e.g., hemihydrate,monohydrate, dihydrate, trihydrate and the like). Hydrates or solvatesof onapristone may be prepared by contacting onapristone with water or asolvent under suitable conditions to produce the hydrate or solvate ofchoice, for example, as described herein.

The onapristone amorphous forms also encompass metabolites ofonapristone amorphous forms. “Metabolite” or “metabolites” refer to anysubstance produced from another substance by metabolism or a through ametabolic process of a living cell or organ.

Any of the amorphous onapristone forms described herein can beadministered or used as starting materials to be administered orally,parenterally (IV, IM, depot-IM, SQ, and depot-SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those of skill in the art are suitable for delivery ofthe onapristone amorphous forms described herein.

The onapristone amorphous compounds can be formulated into suitablepharmaceutical preparations such as tablets, capsules, or elixirs fororal administration or in sterile solutions or suspensions forparenteral administration. The onapristone amorphous compounds describedherein can be formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

In one aspect, about 10 to about 200 mg of the onapristone amorphouscompounds, or a physiologically acceptable salt, pro-drug, or co-crystalthereof can be compounded or used as a starting material for compoundingwith a physiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein compositions or preparations comprising the onapristone amorphouscompounds is such that a suitable dosage in the range indicated isobtained.

In another aspect, the compositions can be formulated in a unit dosageform, each dosage containing from about 1 mg to about 1.2 g, or about2.5 to about 200 mg of the active ingredient. The term “unit dosagefrom” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with one or more suitablepharmaceutical excipients.

In one aspect, one or more of the onapristone amorphous compounds aremixed with or used as starting materials mixed with a suitablepharmaceutically acceptable carrier to form compositions. Upon mixing oraddition of the compound(s), the resulting mixture may be a solution,suspension, emulsion, or the like. Liposomal suspensions may also beused as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. The form of theresulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. In one aspect, the effectiveconcentration is sufficient for lessening or ameliorating at least onesymptom of the disease, disorder, or condition treated and may beempirically determined.

Pharmaceutical carriers or vehicles suitable for administration of theonapristone amorphous compounds described herein include any suchcarriers suitable for the particular mode of administration. Inaddition, the active materials can also be mixed with other activematerials that do not impair the desired action, or with materials thatsupplement the desired action, or have another action. The compounds maybe formulated as the sole pharmaceutically active ingredient in thecomposition or may be combined with other active ingredients.

In another aspect, if the onapristone amorphous compounds exhibitinsufficient solubility, methods for solubilizing may be used. Suchmethods are known and include, but are not limited to, using co-solventssuch as dimethylsulfoxide (DMSO), using surfactants such as TWEEN, anddissolution in aqueous sodium bicarbonate. Derivatives of the compounds,such as salts or prodrugs, may also be used in formulating effectivepharmaceutical compositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

In another aspect, the onapristone amorphous compounds described hereinmay be prepared with carriers that protect them against rapidelimination from the body, such as time-release formulations orcoatings. Such carriers include controlled release formulations, suchas, but not limited to, microencapsulated delivery systems. The activecompound can be included in the pharmaceutically acceptable carrier inan amount sufficient to exert a therapeutically useful effect in theabsence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in known in vitro and in vivo model systems forthe treated disorder.

In another aspect, the onapristone amorphous compounds and compositionsdescribed herein can be enclosed in multiple or single dose containers.The enclosed compounds and compositions can be provided in kits, forexample, including component parts that can be assembled for use. Forexample, an onapristone amorphous compound can be used as a startingmaterial for a lyophilized form and a suitable diluent may be providedas a separated component for combination prior to use. A kit may includeonapristone amorphous compound and a second therapeutic agent forco-administration. The onapristone amorphous compound and secondtherapeutic agent may be provided as separate component parts. A kit mayinclude a plurality of containers, each container holding one or moreunit dose of the onapristone amorphous compounds described herein. Inone aspect, the containers can be adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampoules, vials, and the like forparenteral administration; and patches, medipads, creams, and the likefor topical administration.

The concentration of the onapristone amorphous compound in thepharmaceutical composition will depend on dissolution, absorption,metabolism, and excretion rates of the active compound, the dosageschedule, and amount administered as well as other factors known tothose of skill in the art.

In another aspect, the active ingredient may be administered at once, ormay be divided into a number of smaller doses to be administered atintervals of time. It is understood that the precise dosage and durationof treatment is a function of the disease being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

If oral administration is desired, the compound can be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a glidant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action. The onapristone amorphous compounds can be used, forexample, in combination with an antitumor agent, a hormone, a steroid,or a retinoid. The antitumor agent may be one of numerous chemotherapyagents (e.g., everolimus, trastuzumab, TM1-D, anti-HER2 drugs,bevacizumab, paclitaxel, docetaxel, taxanes, doxorubicin, liposomaldoxorubicin, pegylated liposomal doxorubicin, anthracyclines,anthracenediones, carboplatin, cisplatin, 5-FU, gemcitabine andcyclophosphamide).

In one aspect, solutions or suspensions used for parenteral,intradermal, subcutaneous, or topical application can include any of thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oil, a naturally occurring vegetable oil such assesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerin, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA) or its disodiumsalt; buffers such as acetates, citrates, and phosphates; and agents forthe adjustment of tonicity such as sodium chloride and dextrose.Parenteral preparations can be enclosed in ampoules, disposablesyringes, or multiple dose vials made of glass, plastic, or othersuitable material. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Where administered intravenously, suitable carriers include, but are notlimited to, physiological saline, phosphate buffered saline (PBS), andsolutions containing thickening and solubilizing agents such as glucose,polyethylene glycol, polypropylene glycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known in the art.

In another aspect, the onapristone amorphous compounds may be preparedwith carriers that protect the compound against rapid elimination fromthe body, such as time-release formulations or coatings. Such carriersinclude controlled release formulations, such as, but not limited to,implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid,hydroxyl propyl methyl cellulose (HPMC), other cellulose derivatives,and the like. Methods for preparation of such formulations are known tothose skilled in the art.

In yet another aspect, compounds employed in the methods of thedisclosure may be administered enterally or parenterally. Whenadministered orally, compounds employed in the methods of the disclosurecan be administered in usual dosage forms for oral administration as iswell known to those skilled in the art. These dosage forms include theusual solid unit dosage forms of tablets and capsules as well as liquiddosage forms such as solutions, suspensions, and elixirs. When the soliddosage forms are used, they can be of the sustained release type so thatthe compounds employed in the methods described herein need to beadministered only once or twice daily.

The oral dosage forms can be administered to the patient 1, 2, 3, or 4times daily. The onapristone amorphous compounds described herein can beadministered either three or fewer times, or even once or twice daily.Hence, the onapristone employed in the methods of the disclosure beadministered in oral dosage form. Whatever oral dosage form is used,they can be designed so as to protect the compounds employed in themethods described herein from the acidic environment of the stomach.Enteric coated tablets are well known to those skilled in the art. Inaddition, capsules filled with small spheres each coated to protect fromthe acidic stomach, are also well known to those skilled in the art.

The terms “therapeutically effective amount” and “therapeuticallyeffective period of time” are used to denote treatments at dosages andfor periods of time effective to reduce neoplastic cell growth. As notedabove, such administration can be parenteral, oral, sublingual,transdermal, topical, intranasal, or intrarectal. In one aspect, whenadministered systemically, the therapeutic composition can beadministered at a sufficient dosage to attain a blood level of thecompounds of from about 0.01 μM to about 20 μM. For localizedadministration, much lower concentrations than this can be effective,and much higher concentrations may be tolerated. One of skill in the artwill appreciate that such therapeutic effect resulting in a lowereffective concentration of the ONA amorphous compound may varyconsiderably depending on the tissue, organ, or the particular animal orpatient to be treated. It is also understood that while a patient may bestarted at one dose, that dose may be varied overtime as the patient'scondition changes. In one aspect, the onapristone amorphous compoundscan be used to inhibit the growth of tumors derived from tissueincluding, but not limited to, breast, brain, meningiomas, prostate,ovarian, endometrial, uterine leiomyoma, lung, and uterine tissues.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsemployed in the methods of the disclosure administered, the particularcondition being treated, the severity of the condition being treated,the age, weight, general physical condition of the particular patient,and other medication the individual may be taking as is well known toadministering physicians who are skilled in this art.

EXAMPLES Example 1

Physical Form of Onapristone Compound

The physical form of onapristone, either as the bulk drug substance orin its compositions, was established using X-ray powder diffraction(XRPD). XRPD patterns were obtained using a Rigaku MiniFlex powderdiffraction system, equipped with a horizontal goniometer operating inthe θ/2θ mode. The X-ray source was nickel-filtered Kα emission ofcopper (1.54184 Å). Samples were packed into the sample holder using aback-fill procedure, and were scanned over the range of 3.5 to 40degrees 2θ at a scan rate of 0.5 degrees 2θ/min. Using a dataacquisition rate of 1 point per second, these scanning parameters equateto a step size of 0.0084 degrees 2θ. Calibration of the diffractometersystem was effected using purified talc as a reference material. Theintensity scale for all diffraction patterns was normalized so that therelative intensity of the most intense peak in the pattern equaled 100%.

Example 2

The pH-Cycle Method to Obtain Amorphous Onapristone

The onapristone molecule contains a functional group that is effectivelya substituted aniline:

In one aspect, one would expect this group to be somewhat acidic. Usingthe pKa-Predictor module of the Physical Chemistry Program Suite(Advanced Chemical Laboratories, Toronto, Calif.), the pKa of this groupwas predicted to be 5.30±0.25. Using the predictive solubility module ofthe ACD program, it was determined that the protonated form of thecompound is expected to be fairly soluble in water, while the neutralform is expected to be relatively insoluble in water.

In one aspect, 0.408 g of onapristone (0.91 mmol) was slurried in 25 mLof water, and then 0.5 mL of 2N HCl (1.0 mmol) was added. The solidcompletely dissolved in approximately 5 minutes, whereupon 2.0 mL of 0.5N NaOH (1.0 mmol) was added. The precipitated onapristone wassuction-filtered, and allowed to air-dry overnight.

The XRPD pattern of this product was obtained, and the lack of sharpscattering peaks demonstrated its amorphous character. After the initialcharacterization, the substance was placed in a glass vial, and storedunder ambient conditions (temperature of 22-24° C.). The product wassubsequently obtained after storage under ambient conditions for 25weeks, 43 weeks, and 16.5 months. As shown in FIG. 1, the pH-cycledonapristone remained amorphous over the entire 16.5 month storageperiod.

Example 3

Spray-Drying Method to Obtain Amorphous Onapristone

Two samples of onapristone that had been spray-dried with excipientswere prepared to have the following compositions:Sample ID=SSF-PDS-027-001A comprising 25% onapristone in a matrixconsisting of PVP VA64, and was spray-dried from a solution consistingof 8% w/w solids in methanol.

Sample ID=SSF-PDS-027-OOIB comprising 25% onapristone in a matrixconsisting of HPMCAS-M, and was spray-dried from a solution consistingof 8% w/w solids in methanol.

XRPD patterns of these samples were obtained when initially received andafter 12 weeks, 20 weeks, 36 weeks, and 15 months had elapsed. The XRPDpatterns obtained for sample SSF-PDS-027-001A are collected in FIG. 2,while the XRPD patterns obtained for sample SSF-PDS-027-001B arecollected in FIG. 3.

Examination of FIGS. 2 and 3 reveals that both spray-dried dispersionswere amorphous when initially prepared, and that they both remainedamorphous over the 315 month storage period.

Example 4

Hot-Melt Method to Obtain Amorphous Onapristone

Binary Formulations

Four formulations were prepared to determine if a hot-melt procedure wascapable of producing dispersions containing amorphous onapristone. Theexperimental details associated with these formulations are as follows:

Preparation 1: 0.255 g of onapristone and 0.777 g of Kollidon® 30 wereweighed directly into a 150 mL beaker, and then heated on a hot plateuntil the polymer had melted and the onapristone dissolved in the melt.After that, the beaker and contents were allowed to cool back to roomtemperature, whereupon the glassy solid was broken up and then groundinto a powder. The onapristone content of this sample was 24.7% w/w.

Preparation 2: 0.241 g of onapristone and 0.700 g of polyethylene glycol8000 were weighed directly into a 150 mL beaker, and then heated on ahot plate until the polymer had melted and the onapristone dissolved inthe melt. After that, the beaker and contents were allowed to cool backto room temperature, whereupon the glassy solid was broken up and thenground into a powder. The onapristone content of this sample was 25.6%w/w.

Preparation 3: 0.238 g of onapristone and 0.762 g of polyethylene glycol3350 were weighed directly into a 150 mL beaker, and then heated on ahot plate until the polymer had melted and the onapristone dissolved inthe melt. After that, the beaker and contents were allowed to cool backto room temperature, whereupon the glassy solid was broken up and thenground into a powder. The onapristone content of this sample was 23.8%w/w.

Preparation 4: 0.249 g of onapristone and 0.784 g of polyvinylpyrrolidone K29/32 were weighed directly into a 150 mL beaker, and thenheated on a hot plate until the polymer had melted and the onapristonedissolved in the melt. After that, the beaker and contents were allowedto cool back to room temperature, whereupon the glassy solid was brokenup and then ground into a powder. The onapristone content of this samplewas 24.1% w/w.

The XRPD pattern of formulations containing polyvinyl pyrrolidone (i.e.,preparations 1 and 4) are shown in FIGS. 4 and 5, respectively. Alsoshown in FIGS. 4 and 5 are the XRPD patterns of the same products aftereach had been stored under ambient conditions for time periods of 8weeks and 8.5 months. Since no sharp peaks attributable to crystallineonapristone were detected in the XRPD of the preparations, it isconcluded that the drug substance remained amorphous over the entire 8.5month storage period.

The XRPD pattern of formulations containing polyethylene glycol (i.e.,preparations 2 and 3) are shown in FIGS. 6 and 7. Also shown in FIGS. 6and 7 are the XRPD patterns of the same products after each had beenstored under ambient conditions for time periods of 8-weeks and 8.5months, as well as the XRPD patterns of the polyethylene glycol polymersused to form the products.

In addition to a number of weak scattering features, the XRPD patternsof the PEG polymer products are dominated by two scattering peaks atapproximately 19 and 23 degrees 2θ. All of the polymer peaks wereobserved in the XRPD patterns of the dispersions, but no additionalpeaks attributable to crystalline onapristone were detected in the XRPDpatterns of the preparations. Therefore, the drug substance remainedamorphous over the entire 8.5 month storage period.

Ternary Formulations

Three additional formulations were prepared to determine if theinclusion of varying amounts of polyethylene glycol could produce lessbrittle dispersions for products prepared using the hot-melt procedure.The experimental details associated with these formulations are asfollows:

Preparation 5: 0.258 g of onapristone, 0.202 g of polyvinyl pyrrolidoneK29/32, and 0.543 g of polyethylene glycol 3350 were weighed directlyinto a 150 mL beaker, and then heated on a hot plate until the polymershad melted and the onapristone dissolved in the melt. After that, thebeaker and contents were allowed to cool back to room temperature,whereupon the glassy solid was broken up and then ground into a powder.The onapristone content of this sample was 25.7% w/w, and the PVPcontent in this sample was 27.1% w/w (relative to the total polymerconcentration).

Preparation 6: 0.242 g of onapristone, 0.373 g of polyvinyl pyrrolidoneK29/32, and 0.384 g of polyethylene glycol 3350 were weighed directlyinto a 150 mL beaker, and then heated on a hot plate until the polymershad melted and the onapristone dissolved in the melt. After that, thebeaker and contents were allowed to cool back to room temperature,whereupon the glassy solid was broken up and then ground into a powder.The onapristone content of this sample was 24.2% w/w, and the PVPcontent in this sample was 49.3% w/w (relative to the total polymerconcentration).

Preparation 7: 0.241 g of onapristone, 0.547 g of polyvinyl pyrrolidoneK29/32, and 0.197 g of polyethylene glycol 3350 were weighed directlyinto a 150 mL beaker, and then heated on a hot plate until the polymershad melted and the onapristone dissolved in the melt. After that, thebeaker and contents were allowed to cool back to room temperature,whereupon the glassy solid was broken up and then ground into a powder.The onapristone content of this sample was 24.5% w/w, and the PVPcontent in this sample was 73.5% w/w (relative to the total polymerconcentration). The XRPD patterns of these latter three preparations areshown in FIGS. 8-10, respectively, along with the XRPD patterns of thepolyethylene glycol 3350 excipient. Also shown in FIGS. 8-10 are theXRPD patterns of the same products after each had been stored underambient conditions for time periods of 8 weeks and 8.5 months. The XRPDpatterns of the hot-melt dispersions were dominated by the twoscattering peaks (at approximately 19 and 23 degrees 2θ) associated withthe PEG-3350, but no additional peaks attributable to crystallineonapristone were detected in the XRPD of the preparations. Therefore,the drug substance remained amorphous over the 8 week storage period. Inaddition, all three dispersions were easily dislodged from the beaker,and their rendition into powder was straight-forward.

Example 5

Solution-Phase Method to Obtain Amorphous Onapristone

Binary Formulations

Four formulation systems were prepared to determine if a solution-phaseprocedure was capable of producing dispersions containing amorphousonapristone. Each system was based on the use of a specific polymer, butcontaining different amounts of onapristone. The experimental detailsassociated with these formulations are as follows.

For preparations within the Kollidon® 30 system, the requisite amount ofonapristone and Kollidon® 30 were weighed directly into a 150 mL beaker,and 30 mL of absolute isopropanol was added to the beaker. The contentswere stirred until dissolution was complete, whereupon the solution waspoured into an evaporating dish and allowed to completely air-dry. TheKollidon® 30 preparations had the following compositions:

Nominal Mass Mass Actual Polymer Onapristone Kollidon ® 30 PolymerPercentage Taken (g) Taken (g) Percentage 6 0.0314 0.4734 6.22 12 0.05940.4466 11.74 18 0.0918 0.4178 18.01 24 0.1252 0.3812 24.72The XRPD patterns obtained for the Kollidon® 30 formulation series areshown in FIG. 11. Since no sharp peaks attributable to crystallineonapristone were detected in the XRPD of the preparations, it wasconcluded that the drug substance was amorphous in the products.

For preparations within the polyvinylpyrrolidone K29/32 system, therequisite amount of onapristone and Kollidon® 30 were weighed directlyinto a 150 mL beaker, and 30 mL of absolute isopropanol was added to thebeaker. The contents stirred until dissolution was complete, whereuponthe solution was poured into an evaporating dish and allowed tocompletely air-dry. The polyvinylpyrrolidone K29/32 preparations had thefollowing compositions:

Nominal Mass Mass PVP Actual Polymer Onapristone K29/32 PolymerPercentage Taken (g) Taken (g) Percentage 6 0.0313 0.4717 6.22 12 0.06040.4399 12.07 18 0.0903 0.4087 18.10 24 0.1212 0.3881 23.80The XRPD patterns obtained for the polyvinylpyrrolidone K29/32formulation series are shown in FIG. 12. Since no sharp peaksattributable to crystalline onapristone were detected in the XRPD of thepreparations, it was concluded that the drug substance was amorphous inthe products.

For preparations within the polyethylene glycol 3350 system, therequisite amount of onapristone and polyethylene glycol 3350 wereweighed directly into a 150 mL beaker, and 30 mL of absolute isopropanolwas added to the beaker. The contents were heated and stirred untildissolution was complete, whereupon the solution was poured into anevaporating dish and allowed to completely air-dry. The polyethyleneglycol 3350 preparations had the following compositions:

Nominal Mass Mass Actual Polymer Onapristone PEG 3350 Polymer PercentageTaken (g) Taken (g) Percentage 6 0.0311 0.4651 6.27 12 0.0598 0.440011.96 18 0.0907 0.4127 18.02 24 0.1183 0.3846 23.52The XRPD patterns obtained for the polyethylene glycol 3350 formulationseries are shown in FIG. 13. All of the observed scattering peaks wereassociated with the polyethylene glycol 3350, and no sharp peaksattributable to crystalline onapristone were detected in the XRPD of thepreparations. The drug substance was amorphous in the products.

For preparations within the polyethylene glycol 8000 system, therequisite amount of onapristone and polyethylene glycol 8000 wereweighed directly into a 150 mL beaker, and 30 mL of absolute isopropanolwas added to the beaker. The contents were heated and stirred untildissolution was complete, whereupon the solution was poured into anevaporating dish and allowed to completely air-dry. The polyethyleneglycol 8000 preparations had the following compositions:

Nominal Mass Mass Actual Polymer Onapristone PEG 8000 Polymer PercentageTaken (g) Taken (g) Percentage 6 0.0318 0.4829 6.18 12 0.0628 0.432912.67 18 0.0900 0.4107 17.97 24 0.1174 0.3778 23.71The XRPD patterns obtained for the polyethylene glycol 8000 formulationseries are shown in FIG. 14. All of the observed scattering peaks wereassociated with the polyethylene glycol 8000, and no sharp peaksattributable to crystalline onapristone were detected in the XRPD of thepreparations. The drug substance was amorphous in the products.

Ternary Formulations

Since coprecipitate formulations with superior handling characteristicscan often be prepared through the use of more than one polymer, theKollidon® 30/polyethylene glycol 8000 system was studied to determine ifa solution-phase procedure was capable of producing dispersionscontaining amorphous onapristone. The systems contained a nominal 25%amount of onapristone, and had the following compositions:

Nominal Mass Actual Mass Mass PEG Actual PVP/PEG Onapristone OnapristoneKollidon ® 30 8000 Polymer Percentage Taken (g) Percentage Taken (g)Taken (g) Percentages 26% PVP/ 0.128 24.52 0.103 0.291 PVP = 26.14% 74%PEG PEG = 73.86% 50% PVP/ 0.123 23.61 0.198 0.200 PVP = 49.75% 50% PEGPEG = 50.25% 74% PVP/ 0.123 22.61 0.312 0.109 PVP = 74.11% 26% PEG PEG =25.89%The XRPD patterns obtained for the solution-phase ternary coprecipitateformulations are shown in FIG. 15. All of the observed scattering peakswere associated with the polyethylene glycol 8000, and no sharp peaksattributable to crystalline onapristone were detected in the XRPD of thepreparations. The drug substance was amorphous in the ternary products.

Although the above description refers to particular aspects, it is to beunderstood that these aspects are merely illustrative. It will beapparent to those skilled in the art that various modifications andvariations can be made to the amorphous forms and methods describedherein. Thus, it is intended that the present description includemodifications and variations that are within the scope of the appendedclaims and their equivalents.

1. A method of making a stable amorphous onapristone comprising: mixingonapristone and water to form an onapristone solution; mixing at leastone equivalent of an acid solution with the onapristone solution; mixingat least one equivalent of a base to the onapristone solution mixed withthe at least one equivalent of the acid solution to form the stableamorphous onapristone precipitate, wherein the XPRD pattern of thestable amorphous onapristone precipitate does not produce anysubstantially sharp scatter peaks.
 2. The method of claim 1, wherein theacid solution comprises an acid selected from the group consisting ofhydrochloric acid, nitric acid, and sulfuric acid.
 3. The method ofclaim 1, wherein the base is selected from the group consisting ofsodium hydroxide, potassium hydroxide, and ammonium hydroxide.
 4. Themethod of claim 1, wherein the pH of is reduced to 1 or below whenmixing at least one equivalent of an acid solution with the onapristonesolution and the pH is increased to 10 or above to form the stableamorphous onapristone precipitate.
 5. (canceled)
 6. A compositioncomprising onapristone (25%) in a PVP VA64 copolymer matrix.
 7. A methodof spray drying amorphous onapristone comprising, spray drying thecomposition of claim 6 from a solution comprising about 8% w/w solids inmethanol wherein the onapristone is amorphous.
 8. A compositioncomprising onapristone and a polymer, wherein the polymer ispolyvinylpyrrolidone 30, polyethylene glycol 8000, polyethylene glycol3350, or pyrrolidone K29/32, or any combination thereof.
 9. Thecomposition of claim 8, wherein the composition comprises about 0.255 gof onapristone and about 0.777 g of polyvinylpyrrolidone.
 10. A methodof making amorphous onapristone comprising: heating the composition ofclaim 8 until the polymer and forms a polymer melt and the onapristonedissolves in the polymer melt forming a mixture; and allowing themixture to cool to room temperature and form a glassy solid comprisingamorphous onapristone.
 11. The method of claim 10, wherein when thecomposition comprises polyvinylpyrrolidone 30, the onapristone contentof the glassy solid is about 24% w/w.
 12. (canceled)
 13. The compositionof claim 8, wherein the composition comprises about 0.241 g ofonapristone and about 0.700 g of polyethylene glycol
 8000. 14.(canceled)
 15. The method of claim 10, wherein when the compositioncomprises polyethylene glycol 8000, the onapristone content of theglassy solid is about 25% w/w.
 16. (canceled)
 17. The composition ofclaim 8, wherein the composition comprises about 0.238 g of onapristoneand about 0.762 g of polyethylene glycol
 3350. 18. (canceled)
 19. Themethod of claim 10, wherein when the composition comprises polyethyleneglycol 3350, the onapristone content of the glassy solid is about 23%w/w.
 20. (canceled)
 21. The composition of claim 8, wherein thecomposition comprises about 0.249 g of onapristone and about 0.784 g ofpyrrolidone K29/32.
 22. (canceled)
 23. The method of claim 10, whereinwhen the composition comprises polyvinyl pyrrolidone K29/32, theonapristone content of the glassy solid is about 24% w/w.
 24. Thecomposition of claim 8, wherein the composition comprises onapristone,polyvinyl pyrrolidone K29/32, and polyethylene glycol
 3350. 25. Thecomposition of claim 24, wherein the composition comprises about 0.258 gof onapristone, about 0.202 g of polyvinyl pyrrolidone K29/32, and about0.503 g of polyethylene glycol
 3350. 26. The composition of claim 24,wherein the composition comprises about 0.242 g of onapristone, about0.373 g of polyvinyl pyrrolidone K29/32, and about 0.384 g ofpolyethylene glycol
 3350. 27. The composition of claim 24, wherein thecomposition comprises about 0.241 g of onapristone, about 0.547 g ofpolyvinyl pyrrolidone K29/32, and about 0.197 g of polyethylene glycol3350.
 28. (canceled)